Summary: Researchers have developed engineered people microglia that detect disease-related mind changes and transfer healing protein exactly where needed. Using CRISPR systems, the group programmed these tissues to produce an enzyme that breaks down beta-amyloid plaques just in affected places.
In rat models of Alzheimer’s, the remedy reduced inflammation, preserved cells, and lowered markers of head injury. This novel method may improve treatment for Alzheimer’s and other mental problems by turning immune cells into intelligent, living drug delivery systems.
Important Information:
- Targeted Delivery: Engineered microglia just activate in response to amyloid lesions.
- Medical Impact: Reduced neuroinflammation and preserved synaptic health in rabbits.
- Broad Potential: Adjustable system for treating Alzheimer’s, head cancer, and MS.
Origin: UC Irvine
A new way to provide disease-fighting protein throughout the brain does increase the treatment of Alzheimer’s illness and other neurological issues, according to University of California, Irvine professionals.
By engineering human immune cells called microglia, the researchers have created living cellular “couriers ” capable of responding to brain disease and releasing therapeutic agents exactly where needed.
The National Institutes of Health-supported study, published in Cell Stem Cell, demonstrates for the first time that microglia derived from induced pluripotent stem cells can become physically programmed to detect disease-specific mental changes – like amyloid plaques in Alzheimer’s illness– and then transfer enzymes that help break down those dangerous proteins.
As a result, the cells were able to decrease inflammation, preserve neurons and neural connections, and slow several other hallmarks of neurodegeneration in mice.
For patients and families grappling with Alzheimer’s and related diseases, the findings offer a hopeful glimpse at a future in which microglial-based cell therapies could precisely and safely counteract the ravages of neurodegeneration.
“Delivering biologics to the brain has long been a major challenge because of the blood-brain barrier, ” said Mathew Blurton-Jones, UC Irvine professor of neurobiology and behavior and co-corresponding author on the study.
“We’ve developed a programmable, living delivery system that gets around that problem by residing in the brain itself and responding only when and where it ’s needed. ”
Using CRISPR gene editing, the team modified human microglia to secrete neprilysin – an enzyme known to degrade beta-amyloid – under the control of a promoter that only activates near plaques. The result was a highly targeted and pathology-responsive therapy.
In Alzheimer’s mouse models, these engineered microglia reduced the buildup of beta-amyloid and protected against damage to neurons and synapses, curbed inflammation, and even lowered a biomarker of neuronal injury in the blood.
“Remarkably, we found that placing the microglia in specific brain areas could reduce toxic amyloid levels and other AD-associated neuropathologies throughout the brain, ” said Jean Paul Chadarevian, a postdoctoral scholar in the Blurton-Jones lab and first author on the study.
“And because the therapeutic protein was only produced in response to amyloid plaques, this approach was highly targeted yet broadly effective. ”
In addition to Alzheimer’s, the research explored how human microglia respond in models of brain cancer and multiple sclerosis.
In both cases, the engineered cells adopted unique gene expression profiles– highlighting the potential to tailor them to a variety of central nervous system diseases.
“This work opens the door to a completely new class of brain therapies, ” said Robert Spitale, UC Irvine professor of pharmaceutical sciences and co-corresponding author on the study.
“Instead of using synthetic drugs or viral vectors, we’re enlisting the brain’s immune cells as precision delivery vehicles. ”
The researchers noted that much work remains to translate this platform into human trials, including demonstrating long-term safety and developing methods for scalable manufacturing.
However, because the microglia are derived from induced pluripotent stem cells, they could possibly be produced from a patient’s own cells, reducing the risk of immune rejection.
Hayk Davtyan, Alina L. Chadarevian and Jonathan Hasselmann of UC Irvine, among others, also contributed to the study, which was a collaboration among the university’s Department of Neurobiology & Behavior, Institute for Memory Impairments and Neurological Disorders, and Sue & Bill Gross Stem Cell Research Center.
Funding: Grants from the National Institute on Aging, the California Institute for Regenerative Medicine and Cure Alzheimer’s Fund supported the research.
About microglia
Microglia are immune cells that reside in the central nervous system, including the brain and spinal cord. They act as the brain’s primary line of defense against infection and injury, performing like white blood cells do elsewhere in the body.
Think of microglia as the brain’s own surveillance and cleanup crew. They constantly scan the brain for signs of trouble – like pathogens, damaged cells or toxic proteins – and respond by engulfing and digesting harmful substances in a process called phagocytosis.
Microglia also help regulate inflammation and support neuronal function and plasticity during brain development and aging.
Importantly, in diseases like Alzheimer’s, microglia are found near amyloid plaques ( clumps of toxic proteins ), where they become activated and attempt to surround and clear this toxic debris.
But in chronic disease, their activity can become dysregulated, contributing to neuroinflammation and further neuronal damage. Because of their central role in both protecting and sometimes harming the brain, microglia are a major focus of neurological research and a promising target for therapies.
About this genetics, microglia, and Alzheimer’s disease research news
Author: Thomas Vasich
Source: UC Irvine
Contact: Thomas Vasich – UC Irvine
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins ” by Mathew Blurton-Jones et al. Cell Stem Cell
Abstract
Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins
Widespread delivery of therapeutic proteins to the brain remains challenging.
To determine whether human induced pluripotent stem cell (iPSC)-microglia ( iMG) could enable brain-wide and pathology-responsive delivery of therapeutic cargo, we utilized CRISPR gene editing to engineer iMG to express the Aβ-degrading enzyme neprilysin under control of the plaque-responsive promoter, CD9.
To further determine whether increased engraftment enhances efficacy, we utilized a CSF1R-inhibitor resistance approach. Interestingly, both localized and brain-wide engraftment in Alzheimer’s disease ( AD ) mice reduced multiple biochemical measures of pathology.
However, within the plaque-dense subiculum, reductions in plaque load, dystrophic neurites, and astrogliosis and preservation of neuronal density were only achieved following widespread microglial engraftment.
Lastly, we examined chimeric models of breast cancer brain metastases and demyelination, demonstrating that iMG adopt diverse transcriptional responses to differing neuropathologies, which could be harnessed to enable widespread and pathology-responsive delivery of therapeutics to the CNS.
